Efficacy and safety of Treamid in the rehabilitation of patients after COVID-19 pneumonia: a phase 2, randomized, double-blind, placebo-controlled trial

Background Many patients who recovered from COVID are still suffering from pulmonary dysfunction that can be persistent even for months after infection. Therefore, treatment to prevent irreversible impairment of lung function is needed. Treamid (bisamide derivative of dicarboxylic acid, BDDA) was shown to have anti-inflammatory and antifibrotic effects in animal models of pulmonary fibrosis. This study was designed to assess the safety, tolerability, and efficacy of Treamid in the rehabilitation of patients after COVID pneumonia. The aim was to establish whether Treamid could be effective in ameliorating post-COVID sequelae. Methods The phase 2, randomized, double-blind, placebo-controlled clinical trial was done at 8 medical centers in Russia. Patients with a diagnosis of COVID in the past medical history (with the first symptoms of COVID appear no earlier than 2 months before screening) and having fibrotic changes in the lungs, decreased lung function (percentage of predicted FVC and/or DLCO < 80%), and moderate or severe dyspnea according to mMRC scale were enrolled and randomly assigned in a 1:1 ratio (stratified by the initial degree of lung damage, age, and concomitant chronic diseases) by use of interactive responsive technology to peroral administration of Treamid 50 mg or placebo once a day for 4 weeks. The primary outcome was the proportion of patients who achieved clinically significant improvement in FVC and/or DLCO (defined as a relative increase in FVC of ≥ 10% or a relative increase in FVC in the range of ≥ 5 to < 10% plus a relative increase in DLCO of ≥ 15%) at week 4 compared with baseline. Secondary endpoints included changes from baseline in dyspnea scoring evaluated by the modified Borg and mMRC scales, pulmonary function (FEV1, FVC, FEV1/FVC ratio, DLCO, TLC, FRC), 6-min walk distance, the overall score of the KBILD questionnaire, and the proportion of patients with a reduction in the degree of lung damage assessed by CT scores. This trial was registered on ClinicalTrials.gov (Identifier: NCT04527354). The study was fully funded by PHARMENTERPRISES LLC. Results 12 out of 29 patients (41%) in Treamid group achieved clinically significant improvement in FVC and/or DLCO compared to 5 out of 30 patients (17%) in placebo group (p = 0.036). There was a significant decrease of dyspnea according to modified Borg scale observed in the Treamid group (− 0.9 ± 0.7 vs. − 0.4 ± 0.8, p = 0.018). No significant differences in the adverse events were noted. Exploratory analysis of the female population indicated superiority of Treamid over placebo by decreasing dyspnea and the extent of lung damage as well as increasing TLC. Conclusions 4 weeks oral administration of 50 mg Treamid was associated with clinically significant improvement in the post-COVID patients, evident by an increase in FVC and/or DLCO as well as decreasing dyspnea. Treamid was well tolerated and can be safely administered to patients discharged after COVID. Treamid was more effective in women visible by superior improvement of COVID sequalae after 4 weeks treatment. Considering that female gender is a risk factor associated with the development of post-COVID symptoms, Treamid might offer a pharmacological treatment for long-term sequalae after COVID and supports further investigation in future clinical trials in post-COVID patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-022-03660-9.


Appendixes
Appendix S1 Assessment of dyspnea by the mMRC scale (modified medical research council) [ Image recording, description, and CT conclusion shall be evaluated by the Investigator. Changes in the CT image shall be registered in accordance with the procedure in the primary documentation and in the eCRF. Appendix S11. Linear models for change in modified dyspnea score including baseline value of lung damage (initCT), DLCO (initDLCO) and 6MWD (init6MWD) as covariate and corresponding Treamid superiority in women according to least-squares means differences between Treamid and placebo groups adjusted to two different baseline values (low and high). There were no statistically significant differences in smoking history between the cohorts (Table S13.1).
Most patients (81%) never smoked. Only two patients in the placebo group were smokers. For non-smokers, the clinically significant improvement at the primary endpoint was observed in the Treamid group compared to placebo in ITT and PPS populations (Table S13.2). This is consistent with the result obtained for whole study cohort. Appendix S14. Cardiovascular diseases (hypertension) for Treamid and placebo groups. Approximately one half of the randomized patients had a history of hypertension. However, Stage 3 hypertension was diagnosed only in two patients in the placebo group (Table S14.1). After exclusion of Stage 3 patients, the clinically significant improvement of the primary endpoint was observed in the Treamid group compared to placebo in ITT and PPS populations (Table S14.2). The effect was statistically significant for PPS population and «almost significant» for mITT. Appendix S15. Difference in analyzed parameters change from baseline to week 4 between patients who achieved and did not achieve clinical benefits.
Table S15.1 Difference in analyzed parameters change from baseline to week 4 between patients from mITT population who achieved (responders) and did not achieve (non-responders) clinical benefits from treatment (М ± SD or n (%)).

Parameter
Change  Treamid group who achieved (responders) and did not achieve (non-responders) clinical benefits from treatment (М ± SD or n (%)).  Appendix S16. Exploratory analysis of age, hospitalization time and time after the onset of the first symptoms.  Appendix S17. Rationale for study drug dose selection based on PK/PD models Dose selection for the exploratory clinical study was based on data from PK and preclinical efficacy

Parameter Change from baseline to week 4 Responders Non-responders
studies. An oral dose of 10 mg/kg showed a therapeutic effect in all mouse models studied. Preclinical tissue distribution data showed that daily administration of this dose administered led to mean respiratory concentration of 0.50 -0.75 µM. According to preclinical data, oral administration led to uneven distribution between tissue and blood, resulting in higher concentration in tissues. The concentration measured in blood plasma was about 5 times lower compared to lung tissue. Thus, to describe the pharmacokinetics of the drug, it is reasonable to use a multicompartment model. Drug elimination is well described by a two-compartment model with first-order kinetics for absorption and elimination ( Figure   S16.1) and the ratio of constants k 12 /k 21 >>1.
where Cpred is the predicted plasma concentration of the drug, С(t) -experimentally measured drug concentration in blood plasma.

Randomization Investigator No No
There was discussion about the need to enter accurate data into the IRC, especially data for stratification.
No 9-3 27.11 09-02 The presence of concomitant chronic diseases in patient 09-02 was not taken into account during stratification

Randomization Investigator No No
There was discussion about the need to enter accurate data into the IRC, especially data for stratification The presence of concomitant chronic diseases in patients was not taken into account during stratification

Randomization Investigator No No
There was discussion about the need to enter accurate data into the IRC, especially data for stratification No 11-2 24.11 11-06 The presence of concomitant chronic diseases in patients was not taken into account during stratification

Randomization Investigator No No
There was discussion about the need to enter accurate data into the The presence of concomitant chronic diseases in patients was not taken into account during stratification

Randomization Investigator No No
There was discussion about the need to enter accurate data into the IRC, especially data for stratification No 11-2 24.11 11-17 The presence of concomitant chronic diseases in patients was not taken into account during stratification

Randomization Investigator No No
There was discussion about the need to enter accurate data into the IRC, especially data for stratification No 11-2 24.11 11-06 Patient made visit 3 a day later than the window of the visit envisaged by the schedule of procedures

Visits windows Patient No No
It was discussed with investigators to instruct patients on the timing of visits in order to avoid deviations.
No 11-2 24.11 11-10 Patient made visit 6 a day later than the window of the visit envisaged by the schedule of procedures

Visits windows Patient No No
It was discussed with investigators to instruct patients on the timing of visits in order to avoid deviations.
No 11-2 24.11 11-11 Patient made visit 6 a day later than the window of the visit envisaged by the schedule of procedures The stratification of patients was disturbed. These patients have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed with the principal investigator that stratification must be respected and data must be entered into the IRC more carefully.
No 13-1 20.11 13-10 The stratification of patients was disturbed. These patients have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed with the principal investigator that stratification must be respected and data must be entered into the IRC more carefully.
No 13-1 20.11 13-11 The stratification of patients was disturbed. These patients have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed with the principal investigator that stratification must be respected and data must be entered into the IRC more carefully.
No 13-1 20.11 13-12 The stratification of patients was disturbed. These patients have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed with the principal investigator that stratification must be No  1  2  3  4  5  6  7  8  9 10 11 respected and data must be entered into the IRC more carefully.
13-1 20.11 13-05 The stratification of patients was disturbed. Patients are over 60 years of age and have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed with the principal investigator that stratification must be respected and data must be entered into the IRC more carefully.
No 13-1 20.11 13-06 The stratification of patients was disturbed. Patients are over 60 years of age and have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed with the principal investigator that stratification must be respected and data must be entered into the IRC more carefully.
No 13-1 20.11 13-08 The stratification of patients was disturbed. Patients are over 60 years of age and have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed with the principal investigator that stratification must be respected and data must be entered into the IRC more carefully.
No 13-1 20.11 13-09 The stratification of patients was disturbed. Patients are over 60 years of age and have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed with the principal investigator that stratification must be respected and data must be entered into the IRC more carefully. The stratification of patients was disturbed. These patients have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed with the principal investigator that the data in the IRC must be noted more carefully. The 6 minute walk test was not performed correctly at all visits (patients were stopped after walking 42 metres). The investigator attributed this to the fact that she did not fully understand how to perform this test and did not contact the monitor for clarification.

Protocol procedures Investigator No No
It was discussed with the principal investigator that protocol procedures must be followed and followed correctly.
Yes 18-1 23.11 18-02 B4 in a patient was carried out 1 day late with a deviation. The investigator attributed this to the fact that the referral for admission to hospital could not be made in time.

Protocol procedures Investigator No No
It was discussed with the researcher that visitation windows must be respected.
No 18-1 23.11 18-02 The 6 minute walk test was not performed correctly at all visits (patients were stopped after walking 42 metres). The investigator attributed this to the fact that she did not fully understand how to perform this test and did not contact the monitor for clarification.

Protocol procedures Investigator No No
It was discussed with the principal investigator that protocol procedures must be followed and followed correctly.  1  2  3  4  5  6  7  8  9 10 11 perform this test and did not contact the monitor for clarification. must be followed and followed correctly.
18-1 23.11 18-04 The 6 minute walk test was not performed correctly at all visits (patients were stopped after walking 42 metres). The investigator attributed this to the fact that she did not fully understand how to perform this test and did not contact the monitor for clarification.

Protocol procedures Investigator No No
It was discussed with the principal investigator that protocol procedures must be followed and followed correctly.
Yes 18-1 23.11 18-01 The stratification of patients was disturbed. These patients have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed that stratification in the eIRC needs to be marked more carefully.
No 18-1 23.11 18-02 The stratification of patients was disturbed. These patients have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed that stratification in the eIRC needs to be marked more carefully.
No 18-1 23.11 18-03 The stratification of patients was disturbed. These patients have chronic diseases, and the presence of a risk factor is marked as "no".

Randomization Investigator No No
It was discussed that stratification in the eIRC needs to be marked more carefully.

Visits windows Investigator No No
It was discussed with the principal investigator that the visiting windows must be strictly respected.

Visits windows Investigator No No
It was discussed with the principal investigator that the visiting windows must be strictly respected No  1  2  3  4  5  6  7  8  9  10  11 13-2 11.12 13-04 B7 was carried out with a deviation of 1 week early.

Visits windows Investigator No No
It was discussed with the principal investigator that the visiting windows must be strictly respected No 13-2 11.12 13-02 The patient did not have an FRC body plethysmography score on B1 for technical reasons. Table S5. Rate of relative DLCO and FVC changes in mITT and PPS populations as n (%) and primary efficacy outcome evaluation.